1. Technical Field
The present disclosure is directed to iontophoretic transdermal drug delivery (TDD) systems for pharmaceutically active ingredients and methods of using the same in administration of such ingredients to mammals. More specifically, the TDD system utilizes a porous conductive polyaniline (PANi) membrane as one of two electrodes, with both electrodes in contact with an aqueous solution of the pharmaceutically active ingredient in ionic and nonionic form, and the membrane additionally in contact with the skin surface of the mammal. Upon providing an appropriate direct current flow of electricity by voltage generating means through the electrodes and solution, the pharmaceutically active ingredient is caused to pass through the pores of the membrane and is released in ionic form through the skin surface of the mammal.
2. Background of the Disclosure
While topical drug delivery systems have been used for centuries for the treatment of local skin disorders, the use of the skin as a route for systemic drug delivery is of relatively recent origin. Transdermal administration of drugs has been established in adults in relation to nitroglycerin, estrogens and scopolamine. However, there is a need to develop improved TDD systems which are useful with additional drugs and appropriate for a wider segment of the population.
For a TDD system, the three skin layers of importance are identified as: epidermis, dermis and subcutaneous. The uppermost layer of the epidermis, i.e., the stratum corneum (SC), is the toughest barrier for drug delivery because of its rigid, brick-shaped structure.
Delivery of drugs through a microporous polymeric membrane via aqueous-organic partitioning has been investigated [5-8]. Compared to other conventional controlled release technologies, preparation of such an aqueous-organic partition-based system is convenient and does not require dispersion of the drug into a polymer and the attendant processing steps. Such systems have also been studied in vitro using doxycycline hydrochloride (HCl), a larger (MW: 480.1), polar antibiotic as a model drug with and without mouse skin. In the presence of linoleic acid as a skin transport enhancer, the release rates of this agent were observed to be significant; a simplified mathematical model was developed to successfully describe the experimental data [9].
The prophylactic oral dose of doxycycline is about 700 mg/weekly [10]. If 50% of the drug is bioavailable after the first-pass effect, around 50 mg should be transferred through skin in 24 h. Although the above-noted TDD system using a porous polyvinylidene fluoride (PVDF) membrane [9] can introduce the total amount required in 24 h using appropriate patch dimensions, much faster delivery may be required for other drugs, e.g., lidocaine hydrochloride. Iontophoresis as a means to achieve faster delivery of drug has been researched by the inventors herein to increase the accumulation of drug using a porous polyaniline conducting polymeric membrane as an electrode.
As a non-invasive transdermal drug delivery (TDD) method [1], iontophoresis applies electrical current to deliver solubilized drugs through the skin to either the underlying tissue (local area) or capillaries and then to the whole circulating system (systemically). A voltage applied between two electrodes immersed in a drug solution causes the drug (in the form of charged ions) to be moved from the donor part into the skin. The positively charged electrode, i.e., the anode, attracts the negatively charged drug ions; the negatively charged electrode, i.e., the cathode, attracts the positively charged ions. Usually Ag/AgCl electrodes are used in such a system [2].
There are several advantages to iontophoretic TDD. First, it is a non-invasive way to deliver drug into the body so that great pain is eliminated without mechanical penetration (such as injections) and disruption of the skin. Another advantage is that drugs can be delivered either locally or systemically without potential systemic side effects. As iontophoretic TDD is controlled by the current, the third advantage is that it can also control the timing of drug delivery in an exact fashion which is especially efficient for particular diseases, e.g., Parkinson's disease. Since the current applied is quite low, there is no reason to worry about infection and tissue trauma. However, there are some limitations for iontophoresis, e.g., only water-soluble drugs of molecular weight (MW) under 10,000 (“10,000 Dalton Rule”) are amenable to delivery [3]. In addition, prior art iontophoretic TDD systems have caused in some patients redness, burning and/or itching at the drug administration site. Another concern is the size of the power supply, which ideally should be as small and lightweight as possible. In spite of these limitations, the first pre-filled iontophoretic TDD patch for local anesthesia has been approved by the FDA [4].
Despite efforts to date, a need remains for an effective/reliable transdermal delivery system, particularly for higher molecular weight molecules, e.g., doxycycline hydrochloride (HCl). These and other needs are met by the systems and methods disclosed herein.